No abstract

feelings settle very quickly and majority of them feel improvement in their key respiratory symptoms. Contrary to common perception majority will be happy to have treatment again. Patients felt that a detailed explanation and counselling before starting NIV improves compliance and successful outcome from NIV.

Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we show that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of oxygen status (pseudohypoxia). Whilst TGFβ increased rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting 'bone-type' cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knock down of Factor Inhibiting HIF (FIH) or oxidative stress caused pseudohypoxic HIF activation in normal fibroblasts. In contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of IPF lung mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen-structure function in fibrosis.

Introduction and objectivesNintedanib (OFEV®) is the second drug licensed for the treatment of Idiopathic Pulmonary Fibrosis (IPF). Evidence from the INPULSIS study demonstrated that it reduced annual FVC decline by approximately 50%. Nintedanib has been available in the UK from October 2014 through the Individual Patient Supply Programme (IPSP); initially for those with FVC >50% predicted, latterly available for all with a diagnosis of IPF regardless of FVC. We present preliminary findings of clinical experience with nintedanib in routine UK clinical practice.MethodsA multi-centre, cohort review was undertaken across 6 NHS Trusts. Data were collected from clinical records of individuals receiving nintedanib for the treatment of IPF from October 2014 to July 2015.Results210 patients (161 male) had consented to nintedanib IPSP by July 2015. Mean age (±S. D.) at diagnosis was 70.0 ± 7.7 years. Reasons for starting nintedanib included ineligibility for pirfenidone (FVC >80% predicted: 67 (31.9%) and FVC <50% predicted: 12 (5.7%)), intolerance to pirfenidone 63 (30%), patient preference 54 (25.7%), and clinical progression on pirfenidone 8 (3.8%). Pre-treatment lung function was FVC 72.2 ± 19.0% and DLCO 40.1 ± 17.2% predicted (Domiciliary oxygen was administered to 66 (31.4%) of the cohort.Mean duration of treatment was 2.4 months (range 0 – 8 months) and 78 patients had completed 3-month follow up. Of these 14/78 patients (17.9%) had discontinued nintedanib due to diarrhoea (5 patients), other GI side effects (3), death/lung transplant (2/1), miscellaneous reasons (3). The commonest potential adverse drug reaction (ADR) was diarrhoea occurring in 21/78 (26.9%), which required a dose reduction in 11 patients. Other common ADRs included nausea 11/78 (14.1%), abdominal pain 11/78 (14.1%), decreased appetite 7/78 (9.0%), and weight loss 5/78 (6.4%).ConclusionsThese data demonstrate that at 3 months follow up, Nintedanib is generally well tolerated when used in routine UK practice in patients with IPF across a wide range of FVC’s. The incidence of diarrhoea at 3 months is much lower than the 12 month reported rate in the INPULSIS study. Ongoing longitudinal follow up of this cohort will further inform our understanding of the use of nintedanib for the treatment of IPF.